title: Shp1 regulates T cell homeostasis by limiting IL-4 signals.
abstract: The protein-tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and is generally viewed as a negative regulatory molecule. Mutations in Ptpn6, which encodes Shp1, result in widespread inflammation and premature death, known as the motheaten (me) phenotype. Previous studies identified Shp1 as a negative regulator of TCR signaling, but the severe systemic inflammation in me mice may have confounded our understanding of Shp1 function in T cell biology. To define the T cell–intrinsic role of Shp1, we characterized mice with a T cell–specific Shp1 deletion (Shp1fl/fl CD4-cre). Surprisingly, thymocyte selection and peripheral TCR sensitivity were unaltered in the absence of Shp1. Instead, Shp1(fl/fl) CD4-cre mice had increased frequencies of memory phenotype T cells that expressed elevated levels of CD44. Activation of Shp1-deficient CD4⁺ T cells also resulted in skewing to the Th2 lineage and increased IL-4 production. After IL-4 stimulation of Shp1- deficient T cells, Stat 6 activation was sustained, leading to enhanced Th2 skewing. Accordingly, we observed elevated serum IgE in the steady state. Blocking or genetic deletion of IL-4 in the absence of Shp1 resulted in a marked reduction of the CD44hi population. Therefore, Shp1 is an essential negative regulator of IL-4 signaling in T lymphocytes.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Johnson
authors.forename: Lily I
authors.initials: LI
authors.lastname: Pao
authors.forename: Salim
authors.initials: S
authors.lastname: Dhanji
authors.forename: Kiichi
authors.initials: K
authors.lastname: Murakami
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
mesh_terms: D000818:Animals; D006706:Homeostasis / Q000276:immunology*; D007156:Immunologic Memory; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology
chemical_list: D015847:Interleukin-4; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse